Project Summary/Abstract The developmental period between childhood to adolescence and young adulthood is marked by a mix of potential and vulnerability. A number of potentially life-long behavioral and emotional problems emerge during this critical period, including alcohol and illicit drug use, risky behaviors, and the first signs of emotional disorders. It is important to understand detailed patterns of typical development, so alterations can be identified and rectified as early as possible. As an entirely noninvasive and quantitative imaging method, arterial spin labeled (ASL) perfusion MRI is increasingly being recognized as an important biomarker for functional brain development in both healthy populations and neurodevelopmental disorders. However, there remain significant challenges for making ASL an impactful tool in studying neurodevelopment, including: 1) a coarse spatial resolution of ~4x4x4mm3, 2) susceptibility to head motion with segmented 3D acquisitions, and 3) potential confounding effects of age dependent variations in arterial transit time using a single post-labeling delay (PLD) scan. Simultaneous multi-slice (SMS) or multiband (MB) is a new accelerated imaging technology that simultaneously excites multiple slices and recovers each slice with parallel imaging techniques. Preliminary studies combining MB with ASL showed that MB can reduce T1 relaxation of the label, improve spatial coverage and/or resolution compared to those of standard 2D ASL. MB imaging may also overcome the limitation of 3D ASL acquisitions in terms of head motion and spatial blurring. However, the signal-to-noise ratio (SNR) of existing MB ASL is inferior to that of 3D ASL. This project builds on two recent innovations from our lab: 1) a constrained slice-dependent (CSD) background suppression (BS) technique that improves the SNR of 2D MB pCASL to be comparable to that of 3D pCASL; and 2) a single-shot 3D GRASE pCASL method with 2D CAIPIRINHA accelerations that improves the imaging speed of 3D pCASL. The goal of this R01 project is to develop and evaluate cutting-edge MB pCASL protocols that are able to offer a high spatial resolution of isotropic 2mm or higher, resistance to head motion and multi-delay capability for accurate perfusion quantification in pediatric populations. A convolutional neural network (CNN) based denoising algorithm for multi-delay MB pCASL will be further developed. The developed suite of MB pCASL protocol and post- processing algorithms will be evaluated in 40 typically developing children and adolescents. The successful completion of this R01 project will lead to a robust multi-delay MB pCASL protocol that is highly valuable as potential biomarker for both neurodevelopment research and pediatric clinical care. To maximize the scientific and clinical impact, we will continue disseminating the pulse sequence and associated post-processing software as we have been doing in the past decade.